When sugars are used as medical or agrichemical intermediates and the like, they are produced in a stereoselective manner. In this case, from an industrial viewpoint, it is preferable to efficiently produce a stereoisomers of interest by suppressing generation of stereoisomers other than the original intention. In addition, it may be difficult to obtain a precursor of furanose and/or a furanose derivative, which is used as a starting material. Moreover, such material may be expensive. Thus, it is desirable to develop a method for industrially efficiently producing a furanose derivative having a stereoisomer of interest.
As disclosed in Patent Document 1, Non-Patent Documents 1, 2 and 3, and the like, a nucleic acid derivative obtained by condensing a furanose derivative having a specific configuration and a specific nitrogen-containing heterocyclic compound is extremely useful as a pharmacologically active substance which exhibits an antiviral action or an anticancer action. For example, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose and 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose can be converted to nucleic acid derivatives which are known to be useful as an antiviral agent, such as Clevudine (described in Patent Document 1) or L-Ribavirin (Levovirin) (described in Non-Patent Document 2). Moreover, 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose can be converted to Capecitabine (described in Non-Patent Document 3), for example.
As a furanose derivative to be condensed with a nitrogen-containing heterocyclic compound, there is generally used a furanose derivative in which hydroxyl groups at 1-, 2-, 3- and 5-positions are protected, or a 5-deoxyribofuranose derivative in which hydroxyl groups at 1-, 2- and 3-positions are protected. As such protecting group, an acyl group is generally used because of the easiness of introduction or removal thereof.
For instance, the nucleic acid derivatives exhibiting pharmacological activity disclosed in Patent Document 1 and Non-Patent Documents 2 and 3 are all β-anomers, if the anomeric position of the furanose site thereof is focused. As furanose derivatives used in production of such nucleic acid derivatives, β-anomers are used.
The most commonly used method for synthesizing 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (hereinafter referred to as “β-L-ATBR” at times) that is an example of the furanose derivative of interest of the present invention is a method of converting 2,3,5-tri-O-benzoyl-1-O-methyl-L-ribofuranose (hereinafter referred to as “L-TBM” at times) to β-L-ATBR using acetic anhydride (6.0 equivalents), acetic acid (4.2 equivalents), and sulfuric acid (3 equivalents), which is described in Non-Patent Document 4. However, this method has been problematic in that an α-anomer as a stereoisomer at 1-position of L-ATBR is generated with respect to a β-anomer at a ratio of β/α=65/35, and in that the yield of the β-anomer (β-L-ATBR) is decreased. Moreover, a crude crystal of β-L-ATBR containing a large amount of such α-anomer has crystal properties that are poorer than those of high-purity crude crystal of β-L-ATBR. Thus, when a filtration operation is carried out to produce such crude crystal, filtration ability is poor, and it takes a long period of time to carry out such filtration operation. Hence, production of such crude crystal of β-L-ATBR has been problematic. Furthermore, an excessive amount (6 equivalents) of acetic anhydride is used in this reaction. When this reaction is terminated, the reaction must be terminated by addition of water. However, a large amount of acetic anhydride remains in this method, and thus this method generates a large calorific power. Accordingly, after completion of the reaction, the reaction solution must be slowly added dropwise into water that has been cooled in another vessel, and thus two different reactors are necessary for this reaction. Hence, this method has been industrially problematic.
Methods for producing 1,2,3,5-tetra-O-acetyl-ribofuranose are disclosed in Patent Document 2, and Non-Patent Documents 2, 5 and 6.
In known methods, D- or L-ribose is allowed to react with lower alkanol in the presence of strong acid so as to alkylate the hydroxyl group at 1-position, and the obtained acetal is then treated with acetic anhydride in an acetic acid solvent or in the presence of a base so as to acetylate the hydroxyl groups at 2-, 3- and 5-positions. The subsequent acetolysis is carried out in acetic acid and acetic anhydride in the presence of strong acid.

In Non-Patent Document 5, D-ribose is used as a starting material, the alkylation of the hydroxyl group at 1-position is carried out in methanol in the presence of sulfuric acid, the acetylation is carried out with acetic anhydride in pyridine, and the acetolysis is carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. By recrystallizing from ethanol, 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose is obtained at a total yield of 55%. Moreover, the hydroxyl group at 1-position is methylated, and thereafter, acetylation and the subsequent acetolysis are carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. Thereafter, by recrystallizing from ethanol, 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose is obtained at a total yield of 53%.
In Non-Patent Document 2, L-ribose is used as a starting material, the alkylation of the hydroxyl group at 1-position is carried out in methanol that contains hydrochloric acid, the acetylation is carried out with acetic anhydride in pyridine, and the acetolysis is carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid. By recrystallizing from ethyl ether, 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose is obtained at a total yield of 57%. Hereinafter, in the present specification, 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose may be referred to as β-L-TAR at times, and 1,2,3,5-tetra-O-acetyl-L-ribofuranose may be referred to as L-TAR at times.
In Non-Patent Document 6, L-ribose is used as a starting material, the methylation of the hydroxyl group at 1-position is carried out in methanol in the presence of sulfuric acid, the resultant mixture is then treated with lithium carbonate, the acetylation is then carried out in acetic acid and acetic anhydride, and concentrated sulfuric acid and acetic anhydride are further added thereto to carry out the acetolysis. A crude product is a mixture of α/β-anomers of 1,2,3,5-tetra-O-acetyl-L-ribofuranose. The crude product is treated with water and isopropyl alcohol to obtain 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose at a total yield of 60%.
Herein, with regard to 1,2,3,5-tetra-O-acetyl-ribofuranose, for example, its β-anomer is a solid, and its α-anomer is an oily substance. In order to separate the product of interest from by-products generated in the process of converting ribose to the product of interest and to purify the product of interest, β-anomer that can be recrystallized from an inexpensive solvent or can be purified by washing is advantageous in terms of industrial production.
A ribofuranose having a specific configuration is extremely expensive. Thus, it is desired to convert ribofuranose to a ribofuranose derivative of interest whose hydroxyl groups at 1-, 2-, 3- and 5-positions are protected by acryl groups at a high yield. In the case of prior art techniques, when L-ribofuranose is converted to 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose, for example, the total yield is only 60%. The biggest reason for the considerable low yield of the β-anomer (β-L-TAR) is considered to be generation of α-anomer as well as the β-anomer of interest. The ratio of the two types of anomers generated is β/α=approximately 3/1. Non-Patent Document 6 discloses that such ratio can be improved to β/α=approximately 5/1 by altering the reaction conditions for acetolysis. However, this document describes that the sum of the acetolysis products, namely, the yield of L-TAR including both α- and β-anomers, is decreased under reaction conditions in which the ratio of the two types of anomers generated has been improved to β/α=approximately 5/1. As a result, the yield of isolable β-L-TAR is hardly improved. Thus, it cannot be said that these known methods are sufficient for industrial, efficient and inexpensive production of β-anomer that is useful as an intermediate for production of nucleic acid derivatives.
Moreover, a method for synthesizing 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (hereinafter referred to as “β-D-DTAR” at times in the present specification) is described in Non-Patent Document 7. That is, 1-O-methyl-5-deoxy-D-ribofuranose is induced via 3 steps from a D-ribofuranose derivative in which the hydroxyl groups at 2- and 3-positions of 1-O-methyl-D-ribofuranose are protected by acetonide. Thereafter, the acetylation of the hydroxyl groups at 2- and 3-positions of the 1-O-methyl-5-deoxy-D-ribofuranose is carried out with acetic anhydride in pyridine. The acetolysis of the obtained 2,3-di-O-acetyl-1-O-methyl-5-deoxy-D-ribofuranose is carried out in acetic acid and acetic anhydride in the presence of concentrated sulfuric acid, so as to convert the compound to 1,2,3-tri-O-acetyl-5-deoxy-β-D-ribofuranose (hereinafter referred to as “D-DTAR” at times in the present specification). With regard to D-DTAR, its β-anomer is a solid, and its α-anomer is an oily substance. Thus, in order to separate the product of interest from by-products generated in the process of converting ribose to the product of interest and to purify the product of interest, β-anomer that can be recrystallized from an inexpensive solvent or can be purified by washing is industrially advantageous. However, the anomer ratio of the obtained crude D-DTAR is β/α=3/1. Thus, this has not been a method for efficiently obtaining the β-anomer of interest.    Patent Document 1: JP Patent Publication (Kohyo) No. 9-508394 A (1997)    Patent Document 2: JP Patent Publication (Kohyo) No. 2005-539032 A    Non-Patent Document 1: J. Med. Chem., 11: 1150 (1972)    Non-Patent Document 2: J. Med. Chem., 43: 1019 (2000)    Non-Patent Document 3: Bioorganic & Medicinal Chemistry, 1697 (2000)    Non-Patent Document 4: Helvetica Chimica Acta 1959 (121) 1171-1173    Non-Patent Document 5: Chem. Ind., 547 (1968)    Non-Patent Document 6: Org. Proc. Res. Develop., 9: 583 (2005)    Non-Patent Document 7: J. Med. Chem., 43: 2566 (2000)